Oxohexahydropyrazinoisoquinolines

ABSTRACT

3-OXO-1,3,4,6,7,11B-HEXAHYDRO-910-DIMETHOXY-2HPYRANZINO(2,1-1)ISOQUINOLINES AND 2,4-DIOXO-1,3,4,6,7,11BHEXAHYDRO-9,10-DIMETHOXY-2H -PYRAZINO(2,1-A)ISOQUINOLINES, PREPARED BY CYCLIZATION REACTIONS OF THE CORRESPONDING 1- AMINOMETHYL1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINES AND 1,2,3,4-TETRAHYDRO- 6,7-DIMETHOXY-1-ISOQUINOLINECARBOXAMIDES, RESPECTIVELY, ARE INTERMEDIATES IN THE PREPARATION OF 1,3,4,6,7,11B-HEXAHYDRO-9,10- DIMETHOXY-2H-PYRAZINO(2,1-A)ISOQUINOLINES, WHICH POSSESS SEDATIVE, TRANQUILIZING AND RELATED PHARMACODYNAMIC EFFECTS.

Int. Cl. C0711 51/72 US. Cl. 260-268 TR 14 Claims ABSTRACT OF THE DISCLOSURE 3 oxo-1,3,4,6,7,1lb-hexahydro 9,10 dimethoxy-ZH- pyrazino[2,1-a]isoquinolines and 2,4-dioxo-1,3,4,6,7,11bhexahydro-9,IO-dimethoxy-ZH pyrazino [2,l-a]isoquinolines, prepared 'by cyclization reactions of the corresponding 1 aminomethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolines and 1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamides, respectively, are intermediates in the preparation of 1,3,4,6,7,1lb-hexahydro 9,10 dimethoxy 2H pyrazino [2,1-a]isoquinolines, which possess sedative, tranquilizing and related pharmacodynamic effects.

This application is a division of our copending application Ser. No. 26,767, filed Apr. 8, 1970, now US. Pat. 3,684,813, which is in turn a division of our copending application Ser. No. 826,681, filed May 21, 1969, now US. Pat. 3,557,120, which is in turn a continuation-inpart of our copending application Ser. No. 569,021, filed Aug. 1, 1966 and now abandoned.

The present specification corresponds to the specification of US. Pat. 3,557,120 except for the subject matter relating to imidazoisoquinolines, which was deleted by amendment from the present application, thus accounting for the absence of Formulas II and VII, part D under Preparation of Intermediates and Derivatives Thereof and Examples 1-8 herein.

Our invention relates to derivatives of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, to intermediates for the same, to derivatives of the intermediates and to the preparation thereof.

The novel compounds of this invention are defined by the structural formula in which Y is 1:1 or 1:2 alkylene of up to (and including) six carbon atoms and m is zero, one or two.

More specifically, the compounds of our invention are 2- [phenyl(CH 3 (R ,R )-1,3,4,6,7,1lb-hexahydro- United States Patent 'ice 9,10 dimethoxy-ZH-pyrazino[2,1-a]isoquinolines which, in the free base form, are defined by the formula 1 (6311 Phenyl and 2- [phenyl(CH ]-4-(R ,R )-1,3,4,6,7,1lb-hexahydro-9,10-dimethoxy 2H pyrazino[2,1-a]isoquinolines defined, in the free base form, by the formula (CH Phenyl In each of the Formulas III and W, m has the meanings given hereinabove. The symbols R and R used in Formulas III and IV, represent hydrogen or lower-alkyl of up to (and including) five carbon atoms.

As used herein, the term 1 :1 alkylene means an alkylene group having both free valence bonds on the same carbon atom, as illustrated by, but not limited to, methylene, 1,1-ethylene, 1,1-propylene, 2,2-propylene, 1,1-butylene, 2,2-butylene, 1,1-isobutylene, 1,1-neopentylene, 3,3- hexylene, and the like, and 1 :2 alkylene" means an alkylene group having one free valence bond on one carbon atom and the other on the carbon atom adjacent to the said carbon atom, as illustrated by, but not limited to, 1,2- ethylene, 1,2-propylene, 2,3-butylene, 1,2-isobutylene, 2,3- hexylene, 2,3-isopentylene, 1,2-neohexylene, and the like.

As used throughout, the term lower-alkyl means saturated, monovalent hydrocarbon groups including straight and branched-chain groups as illustrated by, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, and the like. Lower-alkyl groups of from one to three carbon atoms are preferred.

The benzene ring of the terms phenyl, phenyl-loweralkyl, and phenyl((CH as used throughout this disclosure can bear any number and kind of substituents such as would occur to those skilled in the art. The presence of such substituents on the benzene ring does not adversely affect the pharmacological activity of the compositions of this invention. Preferred among such substituted-benzene rings are, Without limiting the generality of the foregoing, monosubstituted phenyl wherein the substituent is in any of the possible orientations in the ring, for example, lower-alkylphenyl, e.g., methylphenyl, ethylphenyl, isopropylphenyl; halophenyl, e.g., fluorophenyl, chlorophenyl, bromophenyl, iodophenyl; loweralkoxyphenyl, e.g., methoxyphenyl, ethoxyphenyl, butoxyphenyl; trifluoromethylphenyl; lower-alkylthiophenyl, e.g., methylthiophenyl, butylthiophenyl; or N,N-di-lower alkylaminophenyl, e.g., N,N-dimethylaminophenyl, N-methyl- N-ethylaminophenyl. [In the aforementioned groups, lower- 3 alkyl or loWer-alkoxy can have from one to four carbon atoms. Thus the term Phenyl in Formulas I, III-VI and VIII-XVIII can be either unsubstituted or substituted by a member of the group consisting of lower-'alkyl, loweralkoxy, halogen, halo-lower-alkyl, lower-alkylthio or N,N-

di-lower-alkylamino.

The term phenyl-lower-alky as used throughout means a monovalent radical consisting of the phenyl nucleus bonded to the rest of the molecule through a divalent lower-alk'ylene radical of from one to four carbon atoms as exemplified by, but not limited to, methylene, 1,1-ethylene, l1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, and the like. Thus, solely for illustration and without limitation, examples, of phenyl-lower-alkyl are phenylmethyl, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, and the like.

Pharmacological evaluation of the compounds of Form ulas III and IV has shown that they possess pharmacodynamic properties, in particular, central nervous system depressing, sedative, and anti-convulsant activities thus indicating their usefulness as C.N.S depressants, sedatives, and anti-convulsants.

C.N.S. depressant activity for the compounds of the instant invention was determined in standard activity cages using the method of Dews, Brit. J. Pharmacol., 8, 46 (1953) in which mice, medicated with the test compounds, are placed in wire mesh cages equipped with a photoelectric cell so adjusted that a mouse breaking the beam activates a magnetic digital counter. Thus the number of times the light beam is broken over a period of time is an indication of the motor activity of the animals, and a reduction in the number of counts in the medicated mice over control groups, run simultaneously, is taken as evidence of psychomotor depressant activity. The dose at which such reduction in motor activity was observed was recorded as the active dose. Thus when administered by the oral route in doses of from about 100 to about 300 milligrams per kilogram of body weight the Z-[phenyl- (CH ]3 -(or 4)-(R ,R )-1,3,4,6,7,11b-hexahydro-9,10- dimethoxy-2H-pyrazino[2,l-a]isoquinolines of Formulas III and IV decreased the spontaneous activity of the mice by about 60 to about 85 percent. The preferred pyrazino- [2 ,l-a]isoquinolines of the instant invention, 2-phenethyl- 1,3,4,'6,7,11b hexahydro 9,10 dimethoxy-ZH-pyrazino- [2,1-a]isoquinoline dihydrochloride, described in Example 11, and 2-phenyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-ZH-pyrazino [2, 1-a1isoquinoline dihydrochloride described in Example 9, were found to decrease spontaneous activity by about 60 percent and about 80 percent respectively at dose levels of 100 mg./kg.

Sedative activity of the compounds was determined using the standard hexobarbital potentiation test which is described briefly as follows. The compounds, in the form of their hydrochloride salts in distilled water, were administered either orally or intraperitoneally into three groups of ten white .Swiss mice at each of three different dose levels graduated in geometric progression in multiples of two. Forty minutes after medication, the animals were each administered a subhypnotic dose of 40 mg./kg. of hexobarbital given either orally (p.o.) or intraperitoneally (i.p.). The animals in each group were then examined every five minutes for a period of fifteen minutes for loss of the righting reflex. The number of animals in each group that suffered loss of the righting reflex for at least one minute was noted, and such compounds were considered active, and the dose which produced loss of the righting reflex in fifty percent of the animals was called the Effective Dose (ED Thus 2-phenyl-1,3,4,6,7,1lbhexahydro 9,10-dimethoxy-2H-pyrazino[2,1-a]isoquinoline described in Example 9' below was found to have an ED50 of Anticonvulsant activity was determined using the standard maximal metnazol-induced seizure procedure described by Goodman et al., J. Pharm. Exp. Therap, 108, 168 (1953). In this procedure, convulsions are induced in untreated mice by the intravenous injection of 50 mg./ kg. of metr'azol. A group of ten mice is pretreated with the substance to be tested thirty minutes before receiving metrazol intravenously, and the animal is considered protected and the drug active if the drug prevents the hindleg tonic extensor component of the seizure. The dose which protects fifty percent of the treated animals for a period of ninety minutes after medication is called the Effective Dose (ED Thus 2-phenethyl-1,3,4,6,7,llb-hexahydro-9,IO-dimethoxy-ZH-pyrazino[2,1-a]isoquinoline dihydrochloride, described in Example 11 below, was found to prevent the hindleg tonic extensor component of the seizure at a dose level of 50 mg./kg. (i.p.) and the ED of 2 phenyl-1,3,4,6,7,l1b-hexahydro-9,IO-dimethoxy-ZH- pyrazino[2,1-a]isoquinoline dihydrochloride, described in Example 9 hereinbelow, was found to be 57 mg./ kg. (i.p.).

The compounds of Formulas IH and IV were found to be pharmacologically active at dose levels well below dose levels manifesting evidence of acute toxicity. I

The actual determination of the numerical biological data definitive for a particular compound is readily obtained by the above-described standard test procedures by technicians trained in pharmacological test methods, without the need for any extensive expermentation.

The intermediate 1-[N-(phenyl(CH ]aminomethyl- 1,2,3,4 tetrahydro 6,7-di-rnethoxyisoquinoline, is repre sented by the formula wherein m is zero, one or two, with a carbonyl compound such as an aldehyde or a ketone.

The intermediate, 1- [N-(phenyl(CH )]aminomethyl 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, of Formula V, can be prepared by lithium aluminum hydride reduction of N- [phenyl(CH -1,2,3,4-tetrahydro-6,7-di

methoxy-l-isoquinolinecarboxamide of the formula in which m is zero, one or two.

The N-[phenyl(CH l l,2,3,4 tetrahydro-6,7-dimethoxyl-isoquinalinecarboxamide (VI) used as an intermediate in preparing the pyrazinoisoquinolines of our invention, is prepared by reacting ethyl 1,2,3,4-tetrahydro-6,7- dimethoxyl-isoquinolinecarboxylate, known in the prior art, with phenyl(CH amine, wherein m has the meanings given hereinabove. The reaction is preferably carried out at a temperature between about 75 C. and 225 C. either Without a solvent or with a solvent inert under the conditions of the reaction. Such solvents are, for example, benzene, toluene, or xylene. It is preferable, but not necessary, to carry out the reaction under an atmosphere ofv nitrogen, and in the presence of a sodium or potassium alkoxide, for example, potassium tert-butoxide.

Alkylated ring-nitrogen derivatives of the intermediate, N [phenyl(CH ]-1,2,3,4-tetrahydro-6,7-dimethoxy-1- isoquinolinecarboxamide, represented by the formula and of the intermediate, 1 [N (pheny1(CH ]aminomethyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline represented by the formula IX CH \CHI as, l H

HaCO

where in both formulas R is lower-alkyl or phenyl-loweralkyl, can be prepared by the reaction of the compounds of Formula VI and Formula V respectively, with loweralkyl and phenyl-loWer-alkyl esters of strong mineral acids. By way of illustration and without being limited thereto, there can be mentioned lower-alkyl chlorides, lower-alkyl bromides, phenyl-lower-alkyl bromides, loweralkyl sulfates, phenyl-lower-alkyl sulfates, and the like. Alternatively, loWer-alkyl and phenyl-lower-alkyl esters of strong organic sulfonic acids can be used, for example, lower-alkyl and phenyl-lower-alkyl methanesulfonates and toluenesulfonates. The reaction is preferably carried out in refluxing acetonitrile in the presence of sodium carbonate.

When 1 [N (phenyl(CH- )]aminomethyl-1,2,3,4- tetrahydro 6,7 dimethoxyisoquinoline (V) is reacted with an u-halo lower-alkanoyl halide at a temperature of about C. to 10 C. in the presence of anhydrous sodium carbonate, and in a solvent inert under the conditions of the reaction, there is obtained l-[N-(a-halo loweralkanoyl) N (phenyl(CH )]aminomethyl-2-(u-halo lower-alkanoyl) 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline of the formula HaCO- X Hahn Pheuyl cludes both straight and branched-chain radicals of from two to six carbon atoms inclusive as illustrated by, but not limited to, a-chloroacetyl, a-bromoacetyl, a-bromopropionyl, a-chlorobutyryl, oz bromo a methylbutyryl, a chloro or methylpropionyl, a-bromohexanoyl, and the like.

The 2 [phenyl(CH 4 (R ,R3)-1,3,4,6,' 7,11bhexahydro 9,10 dimethoxy 2H pyrazino[2,'l-a]isoquinolines (IV) of this invention are prepared by the method shown in the following reactions,'wherein m, R

and R have the meanings given hereinabove, and X is halogen, preferably bromine or chlorine:

The intermediate, V, prepared as described hereinabove, f is reacted with a phenylmethyl halide in the presence of an acid-acceptor, for example, sodium carbonate or potassium carbonate. The reaction is preferably carried out in refluxing acetonitrile. To the resulting 1 [N (phenyl- .(CH ]aminomethyl 2 benzyl 1,2,3,4 tetrahydro- 6,7 dimethoxyisoquinoline (XI), there is then slowly added at a temperature of about --10 C. and a-halo lower-alkanoyl halide in a solvent inert under the conditions of the reaction. Suitable solvents are, for example, chloroform, methyl dichloride or carbon tetrachloride. The 1 [N (a halo lower alkanoyl) N-(phenyl- (CI-I aminomethyl 2 benzyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline hydrohalide thus obtained, is converted to its base, XII, by treatment at a temperature of about 0 C. with aqueous alkali, and said base is then heated in a lower-alkanol comprised of from one to three carbon atoms, for example, methanol, ethanol, or isopropanol. Without isolation, the lower-alkanol solution of the cyclized compound, XHI, can be subjected to debenzylation by catalytic hydrogenolysis to give the 65 carbonyl intermediate XIV, which can be reduced with lithium aluminum hydride to give a compound represented by Formula IV.

The 3 oxo 2 [phenyl(CH ]-4-(R ,R )-1,3,4,6, 7,11b hexahydro 9,10 dimethoxy 2H pyrazino- 70 [2,1-a]isoquinolines of Formula XIV in addition to having utility'as intermediates for the preparation of the 2- [phenyl(CH 4 (R ,R 1,3,4,6,7,l1b-hexahydro- 9,10 dimethoxy 2H pyrazino[2,1-a]isoquinolines of Formula IV, have been found to possess psychornotor depressant activity when tested according to the method of Dews described above. Exemplary of the 3-oxo intermediates represented by Formula XIV possessing this activity is 3 oxo-2-(4-chlorophenyl)-1,3,4,6,7,1lb-hexahydro 9,10 dimethoxy 2H pyraZino[2,l-a]isoquinoline, described under (E)(2) in the section detailing preparation of intermediates hereinbelow. When administered at 300 mg./kg. (p.o.), 3-oxo-2-(4-chlorophenyl) 1,3,4,6,7,l1b hexahydro-9,l-dimethoxy-2H- pyrazino[2,1-'a]isoquinoline decreased spontaneous activity by about 60 percent. I

The 2 [phenyl(CH ]-3-(R ,R )-1,3,4,6,7,1lb-hexahydro 9,10 dimethoxy 2H pyrazino[2,1-a] isoquinolines (III) of our invention can be prepared by lithium aluminum hydride reduction of 1,4-dioxo-2-[phenyl- (CH 3 (R ,R 1,3,4,6,7,11b-hexahydro-9,10- dimethoxy-2H-pyrazino[2,1-a]isoquinoline of the formula wherein m, R and R have the meanings given hereinabove.

The 1,4-dioxo intermediate supra, is prepared by alternate methods, starting with the known ethyl 1,2,3,4-tetrahydro 6,7 dimethoxy 1 isoquinolinecarboxylate. In one of the methods, the ester is reacted with a-halo loweralkanoyl halide, preferably in chloroform solution at a temperature of about C. to about 10 C. followed by refluxing for three to five hours. The ethyl 2-(a-halo lower alkanoyl) 1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate of the formula wherein m is zero, one or two and R and R are hydrogen or lower-alkyl, and X is bromine or chlorine is then reacted with phenyl(CH amine, wherein m has the meanings given above, preferably at a temperature of about 190 C. to 210 C. for a period of thirty to seventy hours in a solvent, inert under the conditions of the reaction to give the 1,4-dioxo intermediate. A preferred solvent is diethylene glycol monoethyl ether.

Another method for the preparation of the 1,4-dioxo intermediate (XV) comprises the reaction of N-[phenyl- (CH 1,2,3,4 tetrahydro 6,7 dimethoxy 1- isoquinolinecarboxamide (VI), described hereinabove, with an a-halo lower-alkanoyl halide in chloroform solution preferably at a temperature of about 10 C. to 10 C. followed by reflux for one to five hours. The N [phenyl(CH 2 (ix-halo lower-alkanoy1)-1,2,3, 4 tetrahydro 6,7 dimethoxy 1 isoquinolinecarboxamide, thus obtained and having the formula HgCO R2 HzCO wherein m, R R and X have the meanings given above, is reacted with sodium hydride in a refluxing hydrocarbon solvent, preferably at a temperature of about 75 C. to-

about C. for one to three hours to obtain the intermediate 1,4 dioxo-Z-[phenyl(CH ]-3-(R ,R )-1,3,4,6, 7, 1 1b heXahydro-9,10-dimethoxy-2I-I-pyrazino[2,1-a]is0- quinoline (XV).

In addition to being useful as intermediates for the preparation of the 2[phenyl(CH ]-3-(R ,R )-1,3,4,6,7, 11b hexahydro 9,10 dimethoxy 2H pyrazino[2,1- a]isoquinolines of Formula III above, the 1,4-dioxo-2- [phenyl(CH 3 (R ,R )-l,3,4,6,7,1lb-hexahydro- 9,10 dimethoxy 2H-pyrazino[2,1-a]isoquinolines of Formula XV have been found to substantially decrease spontaneous activity when tested according to the method of Dews described hereinabove. Thus a preferred member of the group of compounds represented by Formula XV, 1,4 dioxo 2 phenylmethyl 1,3,4,6,7,11b-hexahydro- 9,10 dimethoxy 2H-pyrazino[2,1-a]isoquinoline, described under (F)( 10) in the section detailing preparation of intermediates hereinbelow, was found to decrease spontaneous activity by about 64 percent when administered at a dose level of 300 mg./kg. (p.o.).

The novel compounds of the instant invention are the bases represented by the General Formulas II, III, and IV as well as the intermediate and derivatives of the intermediates represented by the Formulas VVI and VIII- XVII, given hereinabove and the acid-addition salts of said bases, and said acid-addition salts are the full equivalents of the free bases. The compounds of the invention in free base form are converted to the acid-addition salt form by interaction of the base with an aicd. Conversely, the free bases can be regenerated from the acid-addition salt form in the conventional manner, that is by treating the salts with strong aqueous bases, for example, alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates. The bases thus regenerated can then be interacted with the same or a different acid to give the sameor a different acid-addition salt. Thus the novel bases and all of their acid-addition salts are readily interconvertible.

It will thus be appreciated that the general formula shown above not only represents the structural configurations of the bases of our invention but is also representative of the respective structural entity which is common to all of our respective compounds, whether in the form of the free bases or in the form of the acid-addition salts of the bases. We have found that by virtue of this common structural entity, the bases and theiracid-addition salts have inherent pharmacodynamic activity of the type described hereinabove. This inherent pharmacodynamic activity can be used for pharmaceutical purposes by employing either the free bases or the acid-addition salts formed with pharmaceutically-acceptable acids, that is, acids whose anions are innocuous to the animal organism in effective doses of the salts so that beneficial properties inherent in the common structural entity represented by the free bases are not vitiated by side-effects ascribable to the anions.

In utilizing this pharmacodynamic activity of the salts of the invention, we prefer of course to use pharmaceutically-acceptable salts. Although water-insolubility, high toxicity, or lack of crystalline character may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the waterinsoluble or toxic sa'lts can be converted to the corresponding'pharmaceutically-acceptable bases by decomposition of the salt with aqueous base as described above, or alter: natively they can be converted to any desired pharmaceutically-acceptable acid-addition salt by double decomposition reactions involving the anion, for example, by ion-exchange procedures. V 5

Moreover, apart from their usefulness in pharmaceutical applications, our salts are usefulas 'characterizin g or identifying derivatives of the free bases or in isolation or purification procedures. Like all of the acid-addition salts, such characterizing or purification salt derivatives can, if

9 desired, be used to regenerate the pharmaceutically-acceptable free bases by reaction of the salts with aqueous base, or alternatively they can be converted to pharmaceutical-acceptable acid-addition salts by, for example, ionexchange procedures.

It will be appreciated from the foregoing that all of the acid-addition salts of our new bases are useful and valuable compounds, regardless of considerations of solubility, toxicity, physical form, and the like, and are accordingly within the purview of the instant invention.

The novel feature of the compounds of the invention, therefore, resides in the concept of the bases and cationic forms of the 2-[phenyl(CH ]-3-(R ,R )-1,3,4,6,7,llbhexahydro-9,lfl-dimethoxy-ZH-pyrazino[2,1 a]isoquinolines (III) and the 2-[phenyl(CH ]-4-(R ,R )-l,3,4,6, 7- l 1b-hexahydro-9, IO-dimethoxy-ZH-pyrazino [2,1 a]isoquinolines (IV), the intermediates for the preparation thereof, and derivatives of said intermediates (V-VI and VIII-XVII), and not in any particular acid anion associated with the salt forms of the compounds, rather the acid anions, which can be associated in the salt forms, are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with bases. In fact, in aqueous solutions the base form or water-soluble acid-addition salt form of the compounds of the invention both possess a common prot onated cation or ammonium ion.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The compounds can be prepared for use by dissolving, under sterile conditions, a salt form of the compounds in water (or an equivalent amount of a non-toxic acid it the free base is used), or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for use by injection. Alternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administration or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like. Still further the compounds can be formulated for oral administration in aqueous alcohol, glycol, oil solution or oil-water emulsions, or other conventional pharmaceutical excipients.

- The chemical structures of the compounds of the invention are established by their mode of synthesis and are corroborated by the correspondence between calculated values for the elements and values found by chemical analysis and by concordant spectral properties.

. The following procedures and examples will further illustrate specific embodiments of the invention.

PREPARATION OF INTERMEDIATES AND I DERIVATIVES THEREOF (A) N-[phenyl(C'I-I 2 (R) 1,2,3,4 tetrahydro- 6,7-dimethoxy l isoquinolinecarboxamides [V1, R=H; VIII, R=lower-alkyl and phenyl-lower-alkyl; XVIII, R= (a-halo lower-alkanoyl)] (l) A mixture of 2.7 g. (0.01 mole) of ethyl 1,2,3,4- tetrahydro 6,7-dimethoxy-l-isoquinolinecarboxylate and 5.0 ml. (0.05 mole) of aniline was heated to reflux for one and one-half hours while distilling ofi about 3 ml. of solvent. The residue was taken up in 10 ml. of absolute ethyl alcohol and the solution cooled to give N-phenyll,2,3,4t'etrahydro 6,7 dimethoxy 1 isoquinolinecarboxamide which when recrystallized, from absolute ethyl alcohol, melted at 162-165" C. The hydrochloride salt, prepared by treatment of the free base with an ethyl alcohol solution of anhydrous hydrochloric acid, melted at 237.0-245.0 C. (dec.) (corn).

(2) Following the procedure described in (A)( 1) hereinabove, but substituting N,N-dimethyl-p-phenylenediamine, in molar equivalent amount for the aniline used 10 in that procedure, there is otbained N-(4-dimethylaminophenyl) 1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide.

(3) A mixture of 4.0 g. (0.015 mole) of ethyl 1,2,3,4- tetrahydro-6,7 dimethoxy-1-isoquinolinecarboxylate and 10.0 ml. (0.1 mole) of benzylamine was refluxed for seventeen hours. The mixture was taken up in hot ethyl acetate causing N-phenyl-methyl-l,2,3,4-tetrahydro 6,7- dimethoxy-l-isoquinolinecarboxamide to crystallize spontaneously. Upon collection and recrystallization from boiling ethyl acetate, the product, a white solid, melted at -162 C.

(4) When the procedure of (A)(3) described above is used for the reaction of ethyl l,2,3,4-tetrahydro-6,7- dimethoxy 1 isoquinolinecarboxylate with phenylamine, N phenethyl 1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide is obtained.

(5) Using the procedure described in (A)(l) hereinabove, but substituting 4-(methylthio) aniline for the aniline used in that procedure, there is obtained N-(4- methylthiophenyl)-1,2,3,4-tetrahydro 6,7 dimethoxyl-isoquinolinecarboxamide.

(6) A suspension of 10.6 g. (0.04 mole) of ethyl 2,'2,3,4 tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate, 6.4 (0.05 mole) of 4-chloroaniline and 4.9 g. (0.044 mole) of potassium t-butoxide in 40.0 ml. of toluene was stirred and refluxed for six hours. To the mixture was then added 50 ml. of water. After stirring for one-quarter of an hour, all of the solids had dissolved. The layers were separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried (MgSO The solvent was removed and the residual brown oil was taken into 75 ml. of anhydrous ether causing a solid to separate. The solid was collected and recrystallized from boiling absolute ethyl alcohol to give N-(4-chlorophenyl)-l,2,3,4-tetrahydro 6,7 dimethoxyl-isoquinolinecarboxamide as a white solid, M.P. 121.4- 125.8 C. (corn).

(7) Following the procedure of (A)(6) above, but substituting 4-br0mophenylmethylamine for the 4-chloroaniline used in that procedure, there is obtained N-(4- bromophenyl)methyl-1,2,3,4-tetrahydro 6,7-dimethoxyl-isoquinoilnecarboxamide.

8) Substituting 4-rnethylphenylmethylamine in molar equivalent quantity for 4-chloroaniline, in the procedure described in (A)(6) hereinabove, there is obtained N- (4-methylpheny'l-methyl) l,2,3,4 tetrahydro 6,7-dimethoxy-l-isoquinolinecarboxamide.

(9) Reacting ethyl 1,2,3,4 tetrahydro-6,7-dimethoxyl-isoquinolinecarboxylate with 4-methoxyaniline, accordmg to the procedure followed in (A)(6), afiords N- (4-methoxpheny1)-1,2,3,4 tetrahydro 6,7 dimethoxy- 1-isoquinolinecarboxamide.

(10) When 4-butoxyphenethylamine, ethyl l,2,3,4- tetrahydro 6,7 dimethoxy 1 isoquinolinecarboxylate and potassium t-butoxide are reacted in toluene suspenslon according to the procedure of (A) (6) hereinabove, N (4-butoxyphenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy- 1-1soquinolinecarboxamide is obtained.

(11) The reaction of ethyl 1,2,3,4-tetrahydro-6,7- dimethoxy 1 isoquinolinecarboxylate with 3-methoxyphenethylamine and in the presence of potassium t-butox de in a manner analogous to procedure (A)(6) above, produces N (S-methoxyphenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide.

(12) A stirred mixture of 9.36 g. (0.03 mole) of N- phenyl-l,2,3,4 tetrahydro-6,7-dimethoxy l isoquinolmecarboxamide, 6.14 g. (0.033 mole) of methyl p-toluenesulfonate and 3.8 g. (0.036 mole) of sodium carbonate in 75 ml. of acetonitrile was refluxed for four hours. Chloroform and water were added to the cooled reaction mixture and the layers separated. The aqueous layer was extracted with additional chloroform. The chloroform extracts were dried (MgSO and the solvent removed. A white solid remained, which was subjected to recrystal- 11 lization from boiling absolute ethyl alcohol to give N- phenyl-2-methyl-1,2,3,4 tetrahydro 6,7 dimethoxy-lisoquinolinecarboxamide, M.P. 175.0-177.0 C. (corr.).

(13) When ethyl 2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxylate and aniline are caused to react after the procedure of (A)-(1) as described above, N-phenyl-Z-methyl-1,2,3,4-tetrahydro-6,7- dimethoxy-1-isoquinolinecarboxamide, having the same melting point as that obtained in (A)(l2) above, is obtained.

(14) The reaction of N-phenethyl-l,2,3,4-tetrahydro- 6,7-dimethoxy-l-isoquinolinecarboxamide with benzyl chloride in the presence of sodium carbonate, carried out in refluxing acetonitrile, gives N-phenethyl-Z-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxamide.

(15) To a stirred, chilled solution of 5.0 g. (0.016 mole) of N-phenyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1- isoquinolinecarboxamide there was added in portions 2.2 ml. (0.03 mole) of chloroacetyl chloride. The reaction solution was stirred at room temperature for fifteen minutes and was then refluxed for one and one-half hours. Water and ether were added to the cooled reaction solution and the aqueous phase drawn 01f and discarded. The ether layer was washed with water and aqueous sodium carbonate and finally water, after which the ether solution was dried (MgSO The solvent was removed to give N-phenyl-Z-chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide, which upon recrystallization from boiling ethyl acetate was obtained as a white solid, M.P. 1820-1830 C. (dec.) (corr.).

(16) Following the procedure described in (A)-(15) hereinabove, but substituting N-(4-bromophenyl)methyl- 1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxamide for N-phenyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1- isoquinolinecarboxamide and substituting 2-bromo-2- methylpropionyl bromide for chloroacetyl chloride there is obtained N (4-bromophenyl)methyl-2-(2-bromo-2- methylpropionyl)-1,2,3,4-tetrahydro 6,7 dimethoxy-lisoquinolinecarboxamide.

(17) When the above described procedure of (A)-' (15) is followed, substituting N-(4-methoxyphenyl)- 1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxamide for N-phenyl-l,2,3,4-tetrahydro-6,7-dimethoxy-1- isoquinolinecarboxamide and substituting" 2-chloro-3- methylbutyryl chloride for chloroacetyl chloride, there is obtained N-(4-methoxyphenyl)-2-(2-chloro-3-methylbutyryl)-1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamide.

(18) The application of procedure (A)-(15) above to the reaction of N-(4-butoxyphenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide with 2- bromo-2-methylpropionyl bromide, furnishes N-(4- butoxyphenethyl)-2-(2-bromo 2 methylpropio'nyD- 1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarbox amide.

(B) 1-[N-(R N (phenyl(CH ]aminomethyl-Z- (R )-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinolines [V, R and R =H; IX, R =H, R =lower-alkyl; X, R and R (a-halo lower-alkanoyl); XII, R (u-halo lower alkanoyl), R =phenyl-lower-alkyl] (l) A suspension of 3.8 g. (0.1 mole) of lithium aluminum hydride under 250 ml. of tetrahydrofuran was stirred while 16.0 g. (0.052 mole) of N-phenyl-1,2,3,4- tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide was added in portions during three minutes. The mixture was stirred and refluxed for six hours after which the excess lithium aluminum hydride was carefully destroyed by the addition of 10 ml. of water in 25 ml. of tetrahydrofuran. To the mixture was added 150 ml. of methylene dichloride and stirring was efiected for ten minutes. The solids were filtered ofi with the aid of diatomaceous earth and the methylene dichloride solution dried (MgSO The solvent was removed and the residue crystallized from absolute diethyl ether to give 1-(N-phenyl)aminomethyl-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline, M.P. 9197 C. The monohydrochloride salt, prepared by treatment of the free base with an ethyl alcohol solution of anhydrous hydrochloric acid, was obtained as a colorless white solid, M.P. 2060-2080 C. (dec.) (corr.).

(2) When 14.6 g. (0.042 mole) of N-(4-chlorophenyl)-l,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamide is reduced with 3.0 g. (0.08 mole) of lithium aluminum hydride under 200 ml. of tetrahydrofuran, following the procedure of (B)(l) above, there is obtained 1-[N-(4-chlorophenyl)]aminomethyl-1,2,3,4- tetrahydrio-6,7-dimethoxyisoquinoline as a solid, M.P. 79.5-82.5 C. Treating the base with an alcoholic solution of anhydrous hydrochloric acid gives the monohydrochloride salt, a colorless solid, M.P. 186. 0-l9'2.4 C. (dec.) (corr.).

Proceeding in the manner described in (B)-(l), using the appropriate N- [phenyl(CH -2- (R)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide, the following 1-[N-(phenyl(CH )]aminomethyl 2 (R 1,2,3,4-tetrahydro 6,7 dimethoxyisoquinolines are obtained:

(3) l-[N (4 dimethylaminophenyl)]aminomethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(4) 1- [N-(4 methylthiophenyl) ]amiuomethyl-l,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline.

(5) 1-[N-(4 methylphenylmethyl)aminomethyl-1,2, 3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(6) 1- (N-phenethyDamiuomethyl 2 phenylmethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(7) 1-[N-(4 bromophenylmethyl)]methylamino-l,2, 3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(8) 1-[N-(4-butoxyphenethyl)]aminomethyl 1,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline.

(9) 1-[N-(3 methoxyphenethyl)]aminomethy1-l,2,3, 4-tetrahydro-6,7-dimethoxyisoquinoline.

(10) A mixture of 6.8 g. (0.023 mole) of l-(N- phenyl)aminomethyl 1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline, 4.84 g. (0.026 mole) of methyl p-toluenesulphonate, and 3.2 g. (0.03 mole) of sodium carbonate in ml. of acetonitrile was stirred and heated at reflux for four hours. To the cooled reaction mixture was added 'water and ether and the organic layer drawn oil. The aqueous layer was extracted with chloroform and the combined organic extracts dried. The solvent was removed and the residue was taken up in excess ethyl alcohol solution of anhydrous hydrochloric acid. Upon standing, there separated l- (N-phenyl) aminom'ethyl-Z- methyl-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline in the form of the dihydrochloric acid-addition salt, a colorless solid, M.P. 2020-2030 C. (dec.) (corr.), after recrystallization from methanol.

(1 1 When N-phenyl-Z-methyl-1,2,3,4-tetrahydro-6,7- dimethoxy-1-isoquinolinecarboxamide is reduced with lithium aluminum hydride, according to (B)( 1) hereinabove, and the base is treated with excess ethyl alcohol solution of anhydrous hydrochloric acid, there is obtained 1- (N-phenyl)aminomethyl 2 methyl-1,2,3,4-tetrahydro- 6,7-dimethoxyisoquinoline in the form of the dihydrochloric acid-addition salt having the same melting point as that obtained in (B)-(10) above.

(12) Following the procedure of (B)( 10) above, 13.3 g. (0.04 mole) of l-[N-(4-chlorophenyl)]aminomethyl- 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline, 8.2 g. (0.044 mole) of methyl p-toluenesulphonate and 5.3 g. (0.05 mole) of sodium carbonate in ml. of aceto nitrile were reacted to give 1-[N-(4-chlorophenyl)] aminomethyl-2-methyl-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline, a colorless solid, M.P. 78.0-79.0 C., after recrystallization from ether-hexane.

(13) To a solution of 23.84 g. (0.08 mole) of l-(N- phenyl)aminomethyl-l,2,3,4-tetrahydro-6,7 dimethoxyisoquinoline in 250 ml. of acetonitrile and containing 10.6 g. (0.1 mole) of sodium carbonate, there was added during ninety minutes in a dropwise manner 10.54 g. (0.083 mole) of benzyl chloride in 10 m1. of acetonitrile. The reaction mixture was stirred and refluxed for four hours after which it was cooled, followed by the addition of water. The acetonitrile layer was separated and the aqueous phase was extracted with chloroform. The combined organic solutions were dried and upon removal of the solvent the residue was taken up in absolute ethyl alcohol and the solution diluted with anhydrous ether. A solid separated and was collected and dried to. give l-(N-phenyl)aminomethyl-2-phenylmethyl 1,2,3,4 tetrahydro-6,7- dimethoxyisoquinoline, M.P. 102106 C. An acetone solution of the base was treated with an excess of an ethyl alcohol solution of anhydrous hydrochloric acid to give the dihydrochloride salt, a colorless solid, M.P. 212.2- 214.0 C. (dec.) (corr.).

(14) Using the procedure described in (B)(l3) hereinabove, 41.5 g. (0.125 mole) of 1-[N-(4-chlorophenyl) aminomethyl] 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline were treated with 16.5 g. (0.130 mole) of benzyl chloride in 20 ml. of acetonitrile in the presence of 15.9 g. (0.15 mole) of sodium carbonate. The base was treated with an ethyl alcohol solution of anhydrous hydrochloric acid to give 1-[N-(4-chlorophenyl)]aminomethyl-Z-phenylmethyl 1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline dihydrochloride, M.P. 193.0194.6 C. (dec.) (corr.).

Following the procedure of (B)(l3) above and employing the apropriate 1 [N-(phenyl(CH )]aminomethyl-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline, the following 1 [N (phenyl(CH )]aminomethyl-2- phenylmethyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinolines are obtained.

(15) 1 [N (4 butoxyphenethyl)]aminomethyl-2- phenyl methyl 1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline.

16) 1 -[N (4 bromophenylmethyl)]aminomethyl-2- phenyl methyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline.

17) 1 [N- (4- dimethylaminophenyl)]aminomethyl- 2-phenylmethyl 1,2,3,4 tetrahydro 6,7 dimethoxy isoquinoline.

(18) 1 [N 3 methoxyphenethyl)]aminomethyl-2- phenylmethyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline.

(19) An ice bath cooled solution of 15.52 g. (0.04 mole) of l (N phenyl)aminomethyl-Z-phenylmethyl- 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline in 75 ml. of methylene dichloride was treated with 4.0 ml. (0.053 mole) of chloroacetyl chloride over a period of twenty minutes. The cooling bath was removed and after thrity minutes the reaction mixture was refluxed for two hours. The reaction mixture was diluted with an equal volume of absolute ether causing 1-[N-(chloroacetyl)-N- (phenyl)]aminomethyl 2 phenylmethyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline to separate as the monohydrochloride salt, a colorless solid, M.P. 151.0 154.0 C. (corn), after recrystallization from ethylalcohol-ether.

When the procedure of (B)(19) above is followed in reacting the appropriate 1-[N-(phenyl(CH )]aminomethyl 2 phenylmethyl 1,2,3,4 tetrahydro 6,7 dimethoxyisoquinoline with the appropriate a-halo loweralkanoyl halide the following compounds named as the free base form, are obtained:

(20) 1-[N-(2 bromo 2 methylpropionyl)-N-(4- bromo-phenylmethyl)]aminmethyl 2 phenylmethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(21) 1 [N (2 chloro 3 methylbutyryl)-N-(4- butoxy phenethyl)]aminomethyl 2 phenylmethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(22) 1 [N (chloroacetyl N (4-chlorophenyl)] aminomethyl 2 phenylmethyl 1,2,3,4 tetrahydro- 6,7-dimethoxyisoquinoline.

(23) 1 [N (2 chloro 3 methylvaleryl)-N-(3- 14 methoxy phenethyl)]aminomethyl 2 phenylmethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(24) 1'- [N (2-bromo 2 -methylpropionyl)-N-(4- dimethyl-aminophenyl) ]aminomethyl 2 phenylmethyl 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

(25) To a chilled, stirred solution of 2.98 g. (0.01 mole) of l-(N-phenyl)aminomethyl l,2,3,4 tetrahydro- 6,7-dimethoxyisoquinoline in 50 ml. of methylene dichloride containing 2.3 g. (0.022 mole) of sodium carbonate, there was added over seven minutes 1.13 g. (0.01 mole) of chloroacetyl chloride. The cooling bath was removed and the reaction mixture stirred for thirty minutes, followed by reflux for five hours. The reaction was diluted with water and then extracted with an excess of aqueous hydrochloric acid. The organic layer was separated and dried. The solvent was removed and the residue was taken up in hot absolute ethyl alcohol. On standing l-[N- (chloroacetyl) N (phenyl)]aminomethyl 2 -chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline separated, which after collection and recrystallization from boiling absolute ethyl alcohol gave a colorless solid, M.P. 179.0-180.2 C. (dec.) (corr.).

(C) Ethyl 2-(u-halo lower-alkanoyD-1,2,3,5-tetrahydro- 6,7-dimethoxy-1-isoquinolinecarboxylates (XVI) 1) To a stirred solution of 63.0 g. (0.24 mole) of ethyl 1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate in 360 ml. of chloroform there was added during forty-five minutes, 30 ml. (0.40 mole) of chloroacetyl chloride. The cooling bath was removed and stirring continued for one and one-quarter hours after which the reaction was heated at reflux for three hours. The solvent was removed and the residue was taken up in benzene and washed successively with water, aqueous solution of sodium bicarbonate, and finally water. The organic layer was dried and the solvent removed. The residue was taken up in anhydrous ether from which solution ethyl 2-chloroacetyl-1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxylate separated and after collection and recrystallization from boiling absolute ethyl alcohol with the aid of decolorizing charcoal, was obtained as a colorless solid, M.P. -80.684.2 C. (corr.).

(2) Following the procedure described in (C)(1) above, but substituting 2-bromo-Z-methylpropionyl bromide for the chloroacetyl chloride used in that example, there is obtained ethyl 2-(2-bromo-2-methylpropionyl)- 1,2,3,4 tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate.

(3) When 2-chloro-3-methylbutyryl chloride is substi tuted for chloroacetyl chloride as used in (C)(1) hereinabove, there is obtained ethyl 2-(2-chloro-3-methylbutyryl)-1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxylate.

(4) Using the procedure of (C)(1) hereinabove, but substituting 2-bromo-2-methylbutyryl bromide for chloroacetyl chloride in reaction with ethyl 1,2,3,4-tetrahydro- 6,7-dimethoxy-1-is0quinolinecarboxylate, the product obtained is ethyl 2-(2-bromo-2-methylbutyryl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate.

(5) Following the procedure of (C)(1) hereinabove, but substituting 2-chloro-3-methylvaleryl chloride for chloroacetyl chloride used in that example, there is obtained ethyl 2-(chloro-3-methylvaleryl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate.

(E) 3-0xo-2-[pheny1(CH 4 (R ,R )-1,3,4,6,7,11bhexahydro-9,l0-dimethoxy 2H pyrazino[2,1-a]isoquinolines (XIV) (1) A solution of 32 g. of 1-[N-(chloroacetyl)-N- (phenyl)]amiuomethyl-2-phenylmethyl 1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline in ml. of absolute ethyl alcohol was refluxed for sixteen hours. The reaction mixture was then subjected to catalytic hydrogenation using ten percent palladium on charcoal as the catalyst. The catalyst was removed by filtration and the alcohol solution concentrated in vacuo. The residue was dissolved in water and treated with a slight excess of an aqueous solution of sodium hydroxide. The oil that separated was extracted with chloroform, and the chloroform extract dried. The solvent was removed and the residue recrystallized from boiling absolute ethyl alcohol to give 3- x0 2 phenyl-1,3,4,6,7,1lb-hexahydro-9,IO-dimethoxy- ZH-pyrazino[2,1-a1isoquinoline, a colorless solid, M.P. 171.8-173.4 C. (corr.).

(2) Following the procedure described in (E)-(1) above, 1- [N- (chloro acetyl -N- (4-chlorophenyl) aminomethyl-Z-phenylmethyl-l,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline was heated for sixteen hours in absolute ethyl alcohol solution and without isolation, the cyclized product was catalytically reduced to give 3-0xo-2-(4- chlor-ophenyl) l,3,4,6,7,1lb-hexahydro;9,lO-dimethoxy- 2H-pyrazino[2,1-a]isoquinoline, M.P. 175.6179.6 C. (corr.).

(3) Substituting l-[N-(2-bromo-2-methylpropionyl)- N (4-bromophenylmethyl)]aminomethyl-Z-phenylmethy1-1,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline for 1- [N (chloroacetyl)-N(phenyl)Jaminomethyl-Z-phenylmethyl-l,2,3,4-tetrahydro 6,7 dimethoxyisoquinoline, there is obtained by following the procedure of (E)-(1) above, 3-oxo-2-(4-bromophenylmethyl)-4-dimethyl-1,3,4, 6,7,11b-hexa1hydro-9,10-dimethoxy 2H pyrazino[2,1-a] isoquinoline.

(4) Applying the procedure of (E)( 1) hereinabove, to l-[N (2-chloro-3-methylbutyryl)-N-(4-butoxyphenethyl)]aminomethyl-Z-phenylmethyl 1,2,3,4-tetrahydro- 6,7-dimethoxyisoquinoline, gives 3-oxo-2-(4-butoxyphenethyl) 4 isopropyl-1,3,4,6,7,11b-hexahydro-9',10'-dimethoxy-ZH-pyrazino[2,1-a]isoquinoline.

(5) Using the procedure of (E)-(1) hereinabove, but substituting l-[N (2-chloro-2-methylbutyryl)-N-(3-methoxyphenethyl)]aminomethyl 2 phenylmethyl-1,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline for l-[N-(chloroacetyl) -N- (phenyl) aminomethyl-2-phenylmethyl 1,2,3, 4-tetrahydro-6,7-dimethoxyisoquinoline used in that procedure, there is obtained 3-oxo-2-(3-methoxyphenethyl)- 4-methyl 4 ethyl 1,3,4,6,7,11b-heXahydro-9,l0-dimethoXy-2H-pyrazino [2, 1-a]isoquinoline.

(6) When 1-[N-(2 brom-o 2 methylpropionyD-N-(4- dimethylaminophenyl)]aminomethyl 2 phenylrnethyl- 1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline is substituted for 1- [N- (chloroacetyl) -N- (phenyl) aminornethyl- 2-phenylmethyl-1,2,3,4 tetrahydro-6,7-dimethoxyisoquinoline in the procedure of (E)-( 1) described hereinabove, the product obtained is 3-oxo-2-(4-dimethylaminophenyl) 4 dimethyl 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-ZH-pyrazino [2, 1-a]isoquinoline.

( F) 1,4-dioxo-2-[phenyl(CH 3 (R ,R )-1,3,4,6,7, llb-hexahydro 9,10 dimethoxy-ZH-pyrazino[2,1-a] isoquinolines (XV) (1) A mixture of 20.5 g. (0.06 mole) of ethyl 2-chloroacetyl 1,2,3,4 tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate, 14.0 g. (0.15 mole) of aniline and 10 ml. of diethylene glycol monoethyl ether was refluxed for thirty hours. To the cooled reaction mixture was added chloroform, water, and an aqueous solution of hydrochloric acid. The chloroform layer was separated and the aqueous layer extracted with additional fresh chloroform. The combined organic extracts were dried and the solvent removed. The residue was recrystallized successively from absolute ethyl alcohol, ethyl acetate, and absolute ethyl alcohol to give 1,4dioxo-2-phenyl-1,3,4,6, 7,11b-hexahydro 9,10 dimethoxy-ZH-pyrazino[2,1-a] isoquinoline, a pale yellow solid, M.P. 177.2181. C. (corr.).

(2) A mixture of 1.68 g. (0.0043 mole) of N-phenyl-Z- chloroacetyl 1,2,3,4- tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide and 1.0 g. (0.002 mole) of sodium hydride, suspended in 40 ml. of toluene was refluxed for four and one-half hours. To the cooled mixture was carefully added 25 ml. of water and stirring was effected for fifteen minutes. The benzene layer was separated and the aqueouslayer extracted with chloroform. The dried organic layer was then concentrated in vacuo and the residue taken up in boiling absolute ethyl alcohol. 011 cooling 1,4-dioxo-2-phenyl-1,3,4,6,7,1lb-hexahydro- 9,10 dimethoxy-ZH-pyrazino[2,1-a]isoquinoline crystallized and after collection and recrystallization fiom absolute ethyl alcohol was obtained as a pale yellow solid having the same melting point as the material obtained in (F)(l) above.

(3) Following the procedure of (F)(2), butisubstituting N-(4 bromophenyl)methyl-2-(Z-brorno-Z-methylpropionyl)1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamide for N-phenyl-Z-chloroacetyl-1,2,3, 4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamide used in that procedure, there is obtained 1,4-dioxo-2-(4 bro'mophenylmethyl)-3-dimethyl 1,3,4,6,7,11b hexahydro-9,IO-dimethoxy-ZH-pyrazino [2,1-a]isoquinoline.

(4) Applying the procedure of (F)(Z) hereinabove to N-(4 methoxyphenyl)-2-(2-chloro-3-methylbutyryl)- 1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxamide, there is obtained 1,4-dioxo-2-(4-methoxyphenyl)- 3-isopropyl-1,3,4,-6,7,1lb-hexahydro 9,10 dimethoxy- 2H-pyrazino[2,1-a]isoquinoline.

(5) A mixture of 54.7 g. (0.16 mole) of ethyl 2-chloroacetyl-1,2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxylate and 49.2 g. (0.40 mole) of 2-methoxyaniline in 320 ml. of diethylene glycol monoethyl ether was reacted according to the procedure of (F)(l) hereinabove to obtain 1,4-dioxo-2-(2-methoxyphenyl)-1,3,4,6-, 7,1lb-hexahydro 9,10 dimethoxy-ZH-pyrazino[2,1-a] isoquinoline, a colorless solid, M.P. 171.0-174.0 C. (corr.).

(6) Using the procedure of (F)(l) hereinabove, but substituting 3-methoxyaniline for the aniline used in that procedure there was obtained 1,4-diox0-2-(3-methoxyphenyl)-l,3,4,6,7,11b-hexahydro 9,10 dimethoxy-ZH- pyrazino[2,1-a]isoquinoline, a pale yellow solid, M.P. 136-142 C.

(7) Substituting 4-methoxyaniline for aniline and using the procedure of (F)(l) described above, 1,4dioxo-2- (4-methoxyphenyl) 1,3,4,6,7,11b heXahydro-9,10-dimethoxy-ZH-pyrazino[2,1-a]isoquin0line, M.P. 164-160 C. is obtained.

(8) Applying the procedure of (F)-(1)hereinabove, to the reaction of ethyl 2-(2-bromo-2-methylbutyryl)-1,2, 3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxylate with 4-dimethylamin0phenethylamine, there is obtained 1,4-dioxo-2-(4-dimethylaminophenethyl) 3 methyl-3- ethyl 1,3,4,6,7,11b hexahydoro 9,10 dimethoxy-ZH- pyrazino[2,1-a] isoquinoline.

(9) Reaction of ethyl 2-(2-chloro-3-methylvaleryl)-1, 2,3,4-tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxylate with 4 -methylthiophenylmethylamine, according to the procedure (F)(l) hereinabove, gives 1,4-dioxo-2- (4-methylthiophenylmethyl)-3-(2 butyl) 1,3,4,6,7,llbhexahydro 9,10 dimethoxy-ZH-pyrazino [2,1-a]isoquinoline.

(10) When 34.2 g. (0.1 mole) of ethyl 2-chloroacetyl- 1,2,3,4-tetrahydro-6,7-dimethoxy 1 isoquinolinecarboxylate and 26.8 g. (0.25 mole) of benzylamine in 200 ml. of diethylene glycol monoethyl ether are reacted according to the procedure of (F )-(1) described hereinabove, there is obtained 1,4-dioxo-2-phenylmethyl-1,3,4,6,7,11bhexahydro-9,lO-dimethoxy-2H-pyrazino[2,1 a]isoquinoline as a colorless solid, M.P. 131.0132.0 C. (corn) (11) Following the procedure of (F)(l), described above, but substituting phenethylamine for aniline used in that procedure, there is obtained 1,4-dioxo-2-phenethyl-1,3,4,6,7,1lb-hexahydro 9,10 dimethoxy-ZH-pyrazino[2,1-a]isoquinoline as a colorless solid, M.P. 200.5- 205.5 C.

(12) Using the procedure of (F )-(1) hereinabove, but substituting ethyl 2-(2-bromo-2-methylbutyryl)-1,2,3,4-

tetrahydro 6,7 dimethoxy-l-isoquinolinecarboxylate for ethyl 2-chloroacetyl 1,2,3,4 tetrahydro-6,7-dimethoxyl-isoquinolinecarboxylate and substituting 4-chlorophenethylamine for aniline used in that procedure, the product obtained is 1,4-dioxo-2-(4-chlorophenethyl)-3-methyl-3- ethyl- 1,3,4,6,7,11b hexahydro-9,IO-dimethoxy-ZH-pyrazino [2, l-a] isoquinoline.

(13) When N (4 butoxyphenethyl) 2 bromo-Z- methylpropionyl) 1,2,3,4 tetrahydro-6,7-dimethoxy-1- isoquinolinecarboxamide is reacted with sodium hydride, according to the procedure described in (F)-(2) hereinabove, there is obtained, 1,4-dioxo-2-(4-butoxyphenethyl)-3-dimethyl 1,3,4,6,7,11 b hexahydro 9,10 dimethoxy-2-H-pyrazino[2,1-a]isoquinoline.

EXAMPLE 9 A suspension of 4.6 g. (0.12 mole) of lithium aluminum hydride in 200 ml. of tetrahydrofuran was stirred during the addition of 10.3 g. (0.03 mole) of 3-oxo-2- phenyl 1,3,4,6,7,11b hexahydro 9,10 dimethoxy- 2H-pyrazino[2,1-a]isoquinoline. The reaction mixture was then heated at reflux for five hours after which 10 ml. of water in 25 ml. of tetrahydrofuran was added. After hydrolysis, the mixture was stirred with 150 ml. of chloroform and then filtered with the aid of diatomaceous earth. The organic layer was dried (MgSO and the solvent removed. The residue was taken into acetone and the solution treated with an ethyl alcohol solution of anhydrous hydrochloric acid to give 2-phenyl-1,3,4,6,7,11bhexahydro 9,10 dimethoxy 2H pyrazino[2,1 a] isoquinoline dihydrochloride, a light tan solid, M.P. 219.5- 221.0 C. (dec.) (corr.), after recrystallization from ethyl alcohol-ether.

EXAMPLE 10 Employing a procedure similar to that described in Example 9 and using the appropriate 3-oxo-2- [phenyl- (CH 4 (R ,R 1,3,4,6,7,11b hexahydro 9,10- dimethoxy-ZH-pyrazino[2,1-a1isoquino1ine, there are obtained:

(a) 2 (4 chlorophenyl) 1,3,4,6,7,11b hexahydro- 9,10 dimethoxy 2H pyrazino[2,1-a]isoquinoline, M.P. 158.4-160.0 C. (corn).

(b) 2 (4 bromophenylmethyl) 4 dimethyl 1,3,4, 6,7,11b hexahydro 9,10 dimethoxy 2H pyrazino [2,1-a1isoquinoline.

(c) 2 (4 butoxyphenethyl) 4 isopropyl 1,3,4,6, 7,11b hexahydro 9,10 dimethoxy 2H pyrazino [2, 1-a]isoquinoline.

(d) 2 (3 methoxyphenethyl) 4 methyl 4 ethyl- 1,3,4,6,7,11bhexahydro 9,10 dimethoxy 2H pyrazino [2,1-a] iso q-uinoline.

(e) 2 (4 dimethylaminophenyl) 4 dimethyl- 1,3,4,6,7,llb hexahydro 9,10 dimethoxy 2H pyrazino[2,1-a]isoquinoline.

EXAMPLE 11 To a stirred suspension of 3.8 g. (0.1 mole) of lithium aluminum hydride in 150 ml. of tetrahydrofuran was added 7.25 g. (0.019 mole) of 1,4-dioxo-2-phenethyl- 1,3,4,6,7,11b hexahydro 9,10 dimethoxy 2H pyrazino[2,1-a]isoquinoline. The reaction mixture was re fluxed for five hours after which the excess lithium aluminum hydride was decomposed by the addition of 10 ml. of water in 25 ml. of tetrahydrofuran and finally ml. of water. To the mixture, there was then added 200 ml. of chloroform and stirring continued for fifteen minutes. Filtration was carried out with the aid of diatomaceous earth and the organic filtrate dried. The solvent was removed and the residue taken into 25 ml. of absolute ethyl alcohol. The alcohol solution was treated with an ethyl alcohol solution of anhydrous hydrochloric acid to give 2- phenethyl 1,3,4,6,7,11b hexahydro 9,10-dimethoxy-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, an ofl-white solid, M.P. 276.0278.0 C. (dec.) (corr.), after recrystallization from ethyl alcohol.

18 EXAMPLE 12 Following a procedure similar to that described in Example 11, and using the appropriate 1,4-c1ioxo-2-[phenyl- (CH 3 (R ,R 1,3,4,6,7,11b hexahydro 9,10- dimethoxy-2H-pyrazino-[2,l-a]isoquinoline, there are obtained:

(a) 2 phenylmethyl 1,3,4,6,7,l lb hexahydro 9,10- dimethoxy 2H pyrazino[2,1 a]isoquinoline dihydrochloride, M.P. 262.8264.0 (dec.) (corn).

(b) 2 phenyl l,3,4,6,7,11b hexahydro 9,10 dimethoxy 2H pyrazino [2,1 a] isoquinoline dihydrochloride, M.P. 207218 C. (dec.) (corn). A mixed melting point determination of this compound with that obtained by the procedure of Example 9, show no melting point depression.

(c) 2 (2 methoxyphenyl) 1,3,4,6,7,1lb hexahydro 9,10 dimethoxy 2H pyrazino[2,1 a]isoquinoline dihydrochloride, M.P. 2250-2280 C. (dec.) (corn).

((1) 2 (3 methoxyphenyl) 1,3,4,6,7,11b hexahydro 9,10 dimethoxy 2H pyrazino[2,1 a]isoquinoline dihydrochloride, M.P. 198.0-199.8 C. (dec.) (corn).

(e) 2 (4 methoxyphenyl) 1,3,4,6,7,1b hexahydrodro 9,10 dimethoxy 2H pyrazino[2,1 a] isoquinoline dihydrochloride, M.P. 2330-2345 C. (dec.) corr.).

(f) 2 (4 bromophenylmethyl) 3 dimethyl 1,3,4, 6,7,11b hexahydro 9,10 dimethoxy 2H pyrazino [2,1-a]isoquinoline.

(g) 2 (4 methoxyphenyl) 3 isopropyl 1,3,4,6, 7,11b hexahydro 9,10 dimethoxy 2H pyrazino [2,1-a] isoquinoline.

(h) 2 (4 dimethylaminophenethyl) 3 methyl 3- ethyl 1,3,4,6,7,11b hexahydro 9,10 dimethoxy 2H- pyrazino[2,1-a] isoquinoline.

(i) 2 (4 methylthiophenylmethyl) 3 (2 butyl)- 1,3,4,6,7,11b hexahydro 9,10-dimethoxy-2H-pyrazino [2,1-'a]-isoqiunoline.

(j) 2 (4 butoxyphenethyl) 3 dimethyl 1,3,4,6,7, 11b hexahydro 9,10 dimethoxy 2H pyrazino[2,l-a] isoquinoline.

(k) 2 (4 chlorophenethyl) 3 methyl 3 ethyl- 1,3,4,6,7,11b hexahydro 9,10 dimethoxy-2H pyrazino [2,1-a] isoquinoline.

Our new compounds can exist in stereochemically isomeric forms, that is, optical isomers and geometric isomers. If desired, the isolation or the production of a particular streochemical form can be accomplished by application of the general principles known in the prior art.

We claim:

1. 3-oxo 2 [phenyl(CH ]-4-(R ,R )-1,3,4,6,7,1lbhexahydro-9,10-dimethoxy-2H pyrazino[2,1-a]isoquinoline of the formula HzCO wherein m is zero, one or two; R and R are hydrogen or lower-alkyl of one to three carbon atoms and together have no more than three carbon atoms; and Phenyl is unsubstituted or substituted by a group selected from lower-alkyl of one to four carbon atoms, lower-alkoxy of one to three carbon atoms, halogen, lower-alkylthio of one to four carbon atoms or N,N-di-lower-alkylamino wherein each alkyl has one to four carbon atoms.

2. 3-oxo-[2-phenyl(CH 1,3,4,6,7,11b hexahydro- 9,10-dimethoxy-2H-pyrazino [2,1-a] isoquinoline according to claim 1.

3. 3-oxo 2 phenyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy 2H pyrazino[2,1-a.]isoquinoline according to claim 2.

4. 3 oxo 2-phenyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-ZH-pyrazino[2,1-a]isoquinoline wherein Phenyl is unsubstituted phenyl according to claim 3.

5. 3-oxo-2-(4-chlorophenyl) 1,3,4,6,7,11b hexahydro- 9,10-dimethoxy-2H-pyrazino[2,1-a.]isoquinoline according to claim 3.

6. 1,4-dioxo 2 [pheny1(CH ]-3-(R ,R )-1,3,4,6,7, 11b-hexahydro-9,IO-dimethoxy 2H pyrazino[2,l-a]iso quinoline of the formula wherein m is zero, one or two; R and R are hydrogen or lower-alkyl of one to three carbon atoms and together have no more than three carbon atoms; and Phenyl is unsubstituted or substituted by a group selected from lower-alkyl of one to three carbon atoms, lower-alkoxy of one to four carbon atoms, halogen, lower-alkylthio of one to four carbon atoms or N,N-di-lower-alkylamino wherein each alkyl has one to four carbon atoms. I

7. 1,4-dioxo 2 [phenyl(CH ]-1,3,4,-6,7,1lb-hexahydro-9,IO-dimethoxy-ZH-pyrazino[2,1-a]isoquinoline according to claim 6.

8. 1,4-dioxo-2-phenyl 1,3,4,6,7,11b hexahydro-9,10-

dimethoxy-ZH-pyrazino[2,1-a]isoquinoline according to claim 7.

9. 1,4-dioxo 2 phenyl -1,3,4,6,7,11b-hexahydro-9,10- dimethoxy-ZH-pyrazino[2,1-a]isoquinoline wherein Phenyl is unsubstituted phenyl according to claim 8.

10. 1,4-dioxo 2 (Z-methoxyphenyl)-1,3,4,6,7,11bhexahydro 9,10 dimethoxy-ZH-pyrazino[2,1-a1isoquinoline according to claim 8.

11. 1,4-dioxo 2 (3-met hoxyphenyl)-1,3,4,6,7,11b-' UNITED STATES PATENTS 3,151,116 9/1964 De Stevens et a1. 260268 PC 3,393,195 7/1968 Tiesing et a1. 260268 TR 3,557,120 1/1971 Archer et a1. 260288 R OTHER REFERENCES Krejcarek et al.: Chem. Abstr. vol. 70, col. 20324 g (1969).

DONALD G. DAUS, Primary Examiner 

